Project 1: Progesterone mechanisms of action in aging & Alzheimer's. In this Program Project, we jointly hypothesize that the sex steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. Realizing the potential neural benefits of hormone therapy is constrained, at least in part, by our currently limited knowledge of the (1) basic neurobiology of progesterone, (2) the neural response to clinically relevant progestogens, (3) the complex modulatory interactions between progesterone and estrogen and (4) the impact of extended ovarian hormone privation and AD neuropathology on the brain's responsiveness to progesterone and estrogen. The objectives of Project 1 are to determine 1) the neuroprotective potential of progestogens; 2) their associated mechanism of action including progesterone receptor isoform requirements; 3) the impact of age and endocrine status on ovarian hormone-induced mitochondrial function; and 4) determine the impact of Alzheimer's disease pathology progression on gonadal hormone regulated mitochondrial function. To achieve these objectives, we have developed an interactive research plan that capitalizes on the expertise throughout the program project. Consistent with the Specific Aim structure of all projects within the Program, Specific Aim 1 will determine the direct effect of P< on neural survival and mechanisms of action. Specific Aim 2 will determine the neuroprotective efficacy of clinically relevant progestins. Specific Aim 3 will determine P4 regulation of E2-induced neuroprotection. Specific Aim 4 will determine the impact of E2/P4 on mitochondrial function in rat models of human perimenopause and menopause. Specific Aim 5 will determine the impact of E2/P4 on mitochondrial function in the 3xTgAD mouse model of AD. These studies will utilize both in vitro and in vivo models of neuronal function.